Berglund L A, Derendorf H, Simpkins J W
Department of Pharmocodynamics, University of Florida College of Pharmacy, Gainesville 32610.
Endocrinology. 1988 Jun;122(6):2718-26. doi: 10.1210/endo-122-6-2718.
We studied the effects of two ovarian steroid treatments that induce proestrous-like surges in LH secretion on responsiveness to morphine sulfate (MS), as measured by induced hypothermic, antinociceptive, behavioral, and LH secretory changes. Ovariectomized rats received no steroids (OVX), 7.5 micrograms estradiol benzoate 2 days before the experiment (EB), or EB and then 5 mg progesterone 48 h later (EBP). MS administration coincided with the steroid-induced LH hypersecretion that occurs in the EB and EBP rats at 1530-1630 h. Serum LH concentrations were determined 30 min after administration of MS. In OVX and EB rats, MS caused a dose-dependent decrease in serum LH, but even 20 mg/kg MS did not alter serum LH during the EBP-induced LH surge. Brain-mediated morphine-induced analgesia was evaluated in the three steroid treatment groups from measurement of latency to pawlick on a hot plate. EB and EBP rats were less responsive than OVX rats to MS-induced antinociception. EB and EBP rats were also less responsive than OVX animals to the spinal cord-mediated analgesia due to MS, as calculated by tail-flick latency. MS-induced hypothermia revealed a responsiveness order of OVX greater than EB greater than EBP. Whereas MS caused a dose-dependent reduction in locomotor activity in OVX and EB rats, EBP rats showed marked hyperactivity at low MS doses and were less responsive to the suppression of locomotor activity at higher doses. These marked steroid-induced changes in MS responsiveness could not be explained by altered pharmacokinetic disposition of morphine. These data indicate that treatment with EBP, which stimulates a preovulatory-like LH surge, decreases the ability of MS to induce hypothermic, antinociceptive, and behavioral responses and abolishes its capacity to suppress LH release. These effects of gonadal steroids were not observed before the LH surge, which suggests that this surge is linked to the decline in MS sensitivity. Further, the diminished response to MS appears to be a function of the magnitude of the LH surge.
我们研究了两种诱导促性腺激素释放激素（LH）分泌出现类似动情前期激增的卵巢甾体激素处理对硫酸吗啡（MS）反应性的影响，通过诱导体温降低、抗伤害感受、行为变化以及LH分泌变化来衡量。去卵巢大鼠分别接受以下处理：不给予甾体激素（OVX）；实验前2天给予7.5微克苯甲酸雌二醇（EB）；或先给予EB，然后48小时后给予5毫克孕酮（EBP）。MS给药时间与EB组和EBP组大鼠在1530 - 1630时出现的甾体激素诱导的LH分泌过多相一致。在给予MS 30分钟后测定血清LH浓度。在OVX组和EB组大鼠中，MS导致血清LH呈剂量依赖性降低，但即使给予20毫克/千克的MS，在EBP诱导的LH激增期间也不会改变血清LH水平。通过测量热板上舔爪潜伏期，在三个甾体激素处理组中评估脑介导的吗啡诱导的镇痛作用。EB组和EBP组大鼠对MS诱导的抗伤害感受的反应性低于OVX组大鼠。通过甩尾潜伏期计算，EB组和EBP组大鼠对MS诱导的脊髓介导的镇痛作用的反应性也低于OVX组动物。MS诱导的体温降低显示出反应性顺序为OVX组＞EB组＞EBP组。虽然MS在OVX组和EB组大鼠中导致运动活动呈剂量依赖性降低，但EBP组大鼠在低剂量MS时表现出明显的多动，而在高剂量时对运动活动抑制的反应性较低。这些甾体激素诱导的MS反应性的显著变化无法用吗啡药代动力学处置的改变来解释。这些数据表明，用EBP处理刺激类似排卵前的LH激增，会降低MS诱导体温降低、抗伤害感受和行为反应的能力，并消除其抑制LH释放的能力。在LH激增之前未观察到性腺甾体激素的这些作用，这表明这种激增与MS敏感性的下降有关。此外，对MS反应性的降低似乎是LH激增幅度的函数。
